SONOLISIB

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C29H35NO8
Molecular Weight	525.5901
Optical Activity	UNSPECIFIED
Defined Stereocenters	5 / 5
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[H][C@@]12CCC(=O)[C@@]1(C)C[C@@H](OC(C)=O)C3=C2C(=O)C(O)=C4\C(=C/N(CC=C)CC=C)C(=O)O[C@H](COC)[C@]34C

InChI

InChIKey=QIUASFSNWYMDFS-NILGECQDSA-N

InChI=1S/C29H35NO8/c1-7-11-30(12-8-2)14-17-23-26(34)25(33)22-18-9-10-20(32)28(18,4)13-19(37-16(3)31)24(22)29(23,5)21(15-36-6)38-27(17)35/h7-8,14,18-19,21,34H,1-2,9-13,15H2,3-6H3/b17-14+/t18-,19+,21+,28-,29-/m0/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/25605819
Curator's Comment: The description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/18269228 | https://clinicaltrials.gov/ct2/show/record/NCT01252628 | https://www.ncbi.nlm.nih.gov/pubmed/27118441 | https://clinicaltrials.gov/ct2/show/record/NCT01259869 | https://www.ncbi.nlm.nih.gov/pubmed/25605819

Sonolisib (PX-866) is a small-molecule inhibitor of the alpha, gamma, and delta isoforms of phosphoinositide 3-kinase (PI3K) with potential antineoplastic activity. Sonolisib inhibits the production of the secondary messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3) and activation of the PI3K/Akt signaling pathway, which may result in inhibition of tumor cell growth and survival in susceptible tumor cell populations. Inhibition of the PI3K pathway with Sonolisib leads to inhibition of cell growth and decreased activation of downstream targets in GBM, both in vitro and in vivo, using U87–tumor-bearing mice, including Akt, S6, and mTOR. Sonolisib was in phase II clinical trials by Oncothyreon for the treatment of glioblastoma multiforme and castration-resistant prostate cancer (CRPC). It was in phase I/II clinical trials for the treatment of malignant melanoma, non-small cell lung cancer and Head and neck cancer. In clinical trials, Sonolisib was well tolerated, with common side effects being diarrhea, nausea, vomiting, and elevated liver enzymes. However, no recent development has been reported.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
PI3-kinase p110-alpha subunit 41 Target ID: CHEMBL4005 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18269228	Inhibitor 8297		88.0 nM [IC50]
Serine/threonine-protein kinase mTOR 35 Target ID: CHEMBL2842 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18269228	Inhibitor 8297		3100.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Non-small cell lung cancer 206 Sources: https://clinicaltrials.gov/ct2/show/NCT01204099	Primary	Phase II 1132	Unknown Approved Use Unknown
Incurable metastatic colorectal carcinoma 1 Sources: https://clinicaltrials.gov/ct2/show/NCT01252628	Primary	Phase II 1132	Unknown Approved Use Unknown
Glioblastoma 65 Sources: https://clinicaltrials.gov/ct2/show/NCT01259869	Primary	Phase II 1132	Unknown Approved Use Unknown
Advanced melanoma 4 Sources: https://clinicaltrials.gov/ct2/show/NCT01616199	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
0.76 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22693357	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:	17-OH-PX-866 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1.21 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22693357	8 mg single, oral dose: 8 mg route of administration: Oral experiment type: SINGLE co-administered:	17-OH-PX-866 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2.86 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22693357	10 mg 10 times / 2 weeks multiple, oral dose: 10 mg route of administration: Oral experiment type: MULTIPLE co-administered:	17-OH-PX-866 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2.86 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22693357	12 mg 10 times / 2 weeks multiple, oral dose: 12 mg route of administration: Oral experiment type: MULTIPLE co-administered:	17-OH-PX-866 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
4.02 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22693357	8 mg 10 times / 2 weeks multiple, oral dose: 8 mg route of administration: Oral experiment type: MULTIPLE co-administered:	17-OH-PX-866 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
0.73 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22693357	8 mg 1 times / day multiple, oral dose: 8 mg route of administration: Oral experiment type: MULTIPLE co-administered:	17-OH-PX-866 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED
2.39 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22693357	8 mg 1 times / day multiple, oral dose: 8 mg route of administration: Oral experiment type: MULTIPLE co-administered:	17-OH-PX-866 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
2.44 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22693357	16 mg 10 times / 2 weeks multiple, oral dose: 16 mg route of administration: Oral experiment type: MULTIPLE co-administered:	17-OH-PX-866 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
2.7 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22693357	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:	17-OH-PX-866 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
4.88 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22693357	8 mg single, oral dose: 8 mg route of administration: Oral experiment type: SINGLE co-administered:	17-OH-PX-866 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
5.53 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22693357	10 mg 10 times / 2 weeks multiple, oral dose: 10 mg route of administration: Oral experiment type: MULTIPLE co-administered:	17-OH-PX-866 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
6.82 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22693357	12 mg 10 times / 2 weeks multiple, oral dose: 12 mg route of administration: Oral experiment type: MULTIPLE co-administered:	17-OH-PX-866 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
8.77 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22693357	8 mg 10 times / 2 weeks multiple, oral dose: 8 mg route of administration: Oral experiment type: MULTIPLE co-administered:	17-OH-PX-866 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
3.21 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22693357	8 mg 1 times / day multiple, oral dose: 8 mg route of administration: Oral experiment type: MULTIPLE co-administered:	17-OH-PX-866 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED
6.47 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22693357	8 mg 1 times / day multiple, oral dose: 8 mg route of administration: Oral experiment type: MULTIPLE co-administered:	17-OH-PX-866 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
7.91 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22693357	16 mg 10 times / 2 weeks multiple, oral dose: 16 mg route of administration: Oral experiment type: MULTIPLE co-administered:	17-OH-PX-866 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
2.22 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22693357	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		17-OH-PX-866 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
3.88 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22693357	8 mg single, oral dose: 8 mg route of administration: Oral experiment type: SINGLE co-administered:		17-OH-PX-866 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P00DAS2	https://www.1pchem.com/search?query=1P00DAS2
Apollo Scientific	BIP1009	http://www.apolloscientific.co.uk/chemical_results.php?qstext=BIP1009&product_group=%25&search_fieldname=header_search
Chem Scene	CS-0002501	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0002501
ChemShuttle	140544	https://www.chemshuttle.com/catalogsearch/result/?q=140544
MedChem Express	HY-N6775	https://www.medchemexpress.com/search.html?q=HY-N6775&ft=&fa=&fp=
MolPort	MolPort-020-392-498	https://www.molport.com/shop/molecule-link/MolPort-020-392-498
eMolecules	50280561	https://orderbb.emolecules.com/search/#?query=50280561
mcule	MCULE-8786863401	https://mcule.com/MCULE-8786863401/

PubMed

Title	Date	PubMed
Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling.	2004 Jul	15252137
Synthesis and structure-activity relationships of ring-opened 17-hydroxywortmannins: potent phosphoinositide 3-kinase inhibitors with improved properties and anticancer efficacy.	2008 Mar 13	18269228
Cellular and in vivo activity of a novel PI3K inhibitor, PX-866, against human glioblastoma.	2010 Jun	20156803

Patents

Sample Use Guides

In Vivo Use Guide

8mg PO Daily

Route of Administration: Oral

In Vitro Use Guide

The antiproliferative effect of PX-866 on cells growing in culture was determined using the sulforhodamine B assay. U251, U87, LN229, and LN18 glioblastoma cells (3 x 10^5) were plated per well on 60-mm plates (Costar, Cambridge, Massachusetts) and maintained in 10% fetal bovine serum-containing medium overnight. The next day, the cells were treated with 0.4 and 0.8 mM PX-866. Seventy-two hours later, cells were pelleted, resuspended in 1 mL of 50 mg/mL propidium iodide in phosphate-buffered saline (PBS) containing 20 mg/mL RNase for a further 30 minutes, and then analyzed for DNA content using a FACSCalibur Flow Cytometer and CellQuest software (BD Biosciences, San Jose, California) for any cell-cycle change.

Name

Type

Language

SONOLISIB

Official Name

English

sonolisib [INN]

Common Name

English

PX-866

Code

English

(4E)-4-(((BIS(PROP-2-EN-1-YL)AMINO)METHYLIDENE)-6-HYDROXY-1.ALPHA.-(METHOXYMETHYL)-3,7,17-TRIOXO-2-OXAANDROSTA-5,8-DIEN-11.ALPHA.-YL ACETATE

Common Name

English

CYCLOPENTA(5,6)NAPHTHO(1,2-C)PYRAN-2,7,10(1H)-TRIONE, 5-(ACETYLOXY)-1-((DI-2-PROPEN-1-YLAMINO)METHYLENE)-4,4A,5,6,6A,8,9,9A-OCTAHYDRO-11-HYDROXY-4-(METHOXYMETHYL)-4A,6A-DIMETHYL-, (1E,4S,4AR,5R,6AS,9AR)-

Common Name

English

Sonolisib [WHO-DD]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C129825